Interactions of vascular endothelium and insulin-like growth factors (IGFs) are complex and poorly understood. In vivo, the vascular endothelium is involved in transport of IGFs from the bloodstream to tissue. In vitro, endothelial cells have IGF receptors, respond metabolically to IGF, and synthesize several specific IGF binding proteins (IGFBPs). Endothelial cell (EC)-derived IGFBP-4 is a potent inhibitor of collagen and proteoglycan synthesis; when perfused through isolated hearts, IGFBP-4 has unique subendothelial localization in connective tissue elements. The applicant proposes to: 1) identify more completely EC IGFBPs; 2) for EC EGFBP-4, determine mechanisms of inhibitory actions, tissue distribution, and effect of diabetes; 3) determine effect of glycosylation on IGFBP-3 and -4 functional properties; 4) determine regulation of EC IGFBPs in vitro; 5) develop a perfused organ preparation that will allow analysis of effects of specific IGFBPs on IGF bioactivity; and 6) determine effect of diabetes on production of EC IGFBPs and transcapillary permeability to IGF and IGF-IGFBP complexes.